Cognition, behaviour and academic skills after cognitive rehabilitation in Ugandan children surviving severe malaria: a randomised trial.
Infection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes. This parallel group randomised study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-one Ugandan children aged 5 to 12 years with severe malaria were assessed for cognition (using the Kaufman Assessment Battery for Children, second edition and the Test of Variables of Attention), academic skills (Wide Range Achievement Test, third edition) and psychopathologic behaviour (Child Behaviour Checklist) three months after an episode of severe malaria. Twenty-eight were randomised to sixteen sessions of computerised cognitive rehabilitation training lasting eight weeks and 33 to a non-treatment group. Post-intervention assessments were done a month after conclusion of the intervention. Analysis of covariance was used to detect any differences between the two groups after post-intervention assessment, adjusting for age, sex, weight for age z score, quality of the home environment, time between admission and post-intervention testing and pre-intervention score. The primary outcome was improvement in attention scores for the intervention group. This trial is registered with Current Controlled Trials, number ISRCTN53183087. Significant intervention effects were observed in the intervention group for learning mean score (SE), [93.89 (4.00) vs 106.38 (4.32), P = 0.04] but for working memory the intervention group performed poorly [27.42 (0.66) vs 25.34 (0.73), P = 0.04]. No effect was observed in the other cognitive outcomes or in any of the academic or behavioural measures. In this pilot study, our computerised cognitive training program three months after severe malaria had an immediate effect on cognitive outcomes but did not affect academic skills or behaviour. Larger trials with follow-up after a few years are needed to investigate whether the observed benefits are sustained. ISRCTN: ISRCTN53183087.


MR of neuronal migration anomalies.
Migration anomalies are congenital malformations caused by insults to migrating neuroblasts during the third to fifth gestational months. Included in this group are agyria, pachygyria, polymicrogyria, unilateral megalencephaly, schizencephaly, and gray matter heterotopias. Patients who have these conditions present clinically with developmental delay and seizures, and abnormal motor skills are noted in the more severely affected infants. To determine the utility of MR as a method for imaging in these patients, we used MR to evaluate 13 patients who had the full spectrum of migration anomalies. MR was more sensitive than CT in detecting these anomalies because of its better contrast between gray and white matter. We found that MR was particularly more sensitive in detecting schizencephaly, where recognizing the presence of gray matter lining the cleft is critical to distinguishing that disease from porencephaly, and in detecting polymicrogyria, where critical details of cortical architecture are obscured on CT by the overlying bone. Multiplanar capabilities were also found to be essential, since narrow clefts may not be detected when the imaging plane is parallel to the cleft. MR should be the primary imaging method for infants who have seizures or developmental delay.


Cohort study of informal carers of first-time stroke survivors: profile of health and social changes in the first year of caregiving.
Informal carers underpin community care policies. An initial cohort of 105 informal live-in carers of new stroke patients from the South Coast of England was followed up before discharge, six weeks after discharge and 15 months after stroke with face-to-face interviews assessing physical and psychological health, and social wellbeing. The carer cohort was compared to a cohort of 50 matched non-carers over the same time period. Carer distress was common (37-54%), started early on in the care-giving experience and continued until 15 months after stroke. Carers were 2.5 times as likely as non-carers to have significant psychological distress. Presence of early distress predicted 90% of those significantly distressed 15 months after stroke. Female carers were likely to develop distress earlier than male carers and in anticipation of the care-giving situation. Male carers developed similar levels of distress but only once the care-giving situation became reality. Further research is needed to establish ways to screen for psychological distress early after onset of caregiving, to find ways to tailor proven support interventions to the individual carer, and to evaluate the effect of early detection and support provision on later carer distress.


Metabolism and disposition of bisphenol A in female rats.
Bisphenol A (BPA), which is used in the manufacture of polycarbonates, elicits weak estrogenic activity in in vitro and in vivo test systems. The objectives of this study were to compare the patterns of disposition of radioactivity in adult female F-344 and CD rats after oral administration of (14)C BPA (100 mg/kg), to isolate the glucuronide of BPA and to assess its estrogenic activity in vitro, and to evaluate the transfer of radioactivity to pups from lactating dams administered (14)C BPA. Over 6 days, F-344 rats excreted more radioactivity in urine than CD rats. The major metabolite in urine was identified as bisphenol A glucuronide (BPA gluc) by incubation with beta-glucuronidase and (1)H and (13)C NMR spectroscopy. In lactating CD rats administered (14)C BPA (100 mg/kg) by gavage, only a small fraction of the label was found in milk, with 0.95 +/- 0.66, 0.63 +/- 0.13, and 0.26 +/- 0.10 microg equiv/ml (mean +/- SD) from dams collected 1, 8, and 26 h after dosing, respectively. Radioactivity in pup carcasses indicated exposure in the range of microgram equivalents per kilogram; those values ranged from 44.3 +/- 24.4 for pups separated from their lactating dams at 2 h to 78.4 +/- 10.9 at 24 h. BPA gluc was the prominent metabolite in milk and plasma. In test systems for activation of in vitro estrogen receptors alpha and beta, BPA gluc did not show appreciable efficacy at concentrations up to 0.03 mM, indicating that metabolism via glucuronidation is a detoxication reaction.


Li deposition and desolvation with electron transfer at a silicon/propylene-carbonate interface: transition-state and free-energy profiles by large-scale first-principles molecular dynamics.
We report the result of a large-scale first-principles molecular dynamics simulation under different electric biases performed to understand the charge transfer process coupling with lithium deposition and desolvation processes. We applied the effective screening medium (ESM) method to control the bias across the electrode/solution interface, and simulated a series of Li de-solvation and Li-deposition reactions occurring under the bias. Solvated Li+ in the bulk propylene carbonate migrates to the Si electrode surface and gradually de-solvates through the transition state. Introducing the blue-moon ensemble method, we determined the possible structures and activation energies for the transition states.


Bayesian meta-analysis for longitudinal data models using multivariate mixture priors.
We propose a class of longitudinal data models with random effects that generalizes currently used models in two important ways. First, the random-effects model is a flexible mixture of multivariate normals, accommodating population heterogeneity, outliers, and nonlinearity in the regression on subject-specific covariates. Second, the model includes a hierarchical extension to allow for meta-analysis over related studies. The random-effects distributions are decomposed into one part that is common across all related studies (common measure), and one part that is specific to each study and that captures the variability intrinsic between patients within the same study. Both the common measure and the study-specific measures are parameterized as mixture-of-normals models. We carry out inference using reversible jump posterior simulation to allow a random number of terms in the mixtures. The sampler takes advantage of the small number of entertained models. The motivating application is the analysis of two studies carried out by the Cancer and Leukemia Group B (CALGB). In both studies, we record for each patient white blood cell counts (WBC) over time to characterize the toxic effects of treatment. The WBCs are modeled through a nonlinear hierarchical model that gathers the information from both studies.


Ruptured middle cerebral artery aneurysms with a concomitant intraparenchymal hematoma: the role of hematoma volume.
To study whether clinical outcome data from our patient cohort could give support to the new recommendation in the AHA/ASA guidelines for the management of aneurysmal subarachnoid hemorrhage that states "that microsurgical clipping may receive increased consideration in patients with ruptured middle cerebral artery (MCA) aneurysms and large (>50 mL) intraparenchymal hematomas", while clinical outcome data supporting this recommendation are sparse. We reviewed the clinical and radiological data of 81 consecutive patients with MCA aneurysms and concomitant hematomas admitted between January 2006 and December 2015. The relation between (semi-automatically quantified) hematoma volume (< or > 50 ml), neurological condition on admission (poor: GCS < 8 or non-reactive pupils), treatment strategies (no treatment, coiling, or clipping with or without decompression and/or clot removal), and outcome (favorable: mRS score 0-3) was evaluated. Clinical outcome data were available for 76 patients. A significant difference in favorable outcome (17 vs 68%) was seen when comparing patients with poor and good neurological condition on admission (p < 0.01). Patients with hematomas > 50 ml had similar outcomes for coiling and clipping, all underwent decompression. Patients with hematomas < 50 ml did not show differences in favorable outcome when comparing coiling and clipping with (33 and 31%) or without decompression (90 and 88%). Poor neurological condition on admission, and not large intraparenchymal hematoma volume, was associated with poor clinical outcome. Therefore, even in patients with large hematomas, the neurological condition on admission and the aneurysm configuration seem to be equally important factors to determine the most appropriate treatment strategy.


The personal internetworked notary and guardian.
In this paper, we propose a secure, distributed and scaleable infrastructure for a lifelong personal medical record system. We leverage on existing and widely available technologies, like the Web and public-key cryptography, to define an architecture that allows patients to exercise full control over their medical data. This is done without compromising patients' privacy and the ability of other interested parties (e.g. physicians, health-care institutions, public-health researchers) to access the data when appropriately authorized. The system organizes the information as a tree of encrypted plain-text XML files, in order to ensure platform independence and durability, and uses a role-based authorization scheme to assign access privileges. In addition to the basic architecture, we describe tools to populate the patient's record with data from hospital databases and the first testbed applications we are deploying.


Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients.
Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly. Eight patients treated with a 500 mg/m(2) PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model. The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V(central)) 23.2 L and peripheral volume distribution (V(peripheral)) 10.6 L, and the area under the curve was 186 μg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h. Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.


Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).
Epigenetic events have emerged as key mechanisms in the regulation of critical biological processes and in the development of a wide variety of human malignancies, including gastric cancer (GC), however precise gene targets of aberrant DNA methylation in GC remain largely unknown. Here, we have combined pyrosequencing-based quantitative analysis of DNA methylation in 98 GC cases and 64 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in cancer tissue and non-tumorigenic adjacent tissue of an independent series of GC samples. A panel of 10 cancer-associated genes (CHRNA3, DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and LINE-1 repetitive elements were included in the analysis and their association with clinicopathological characteristics (sex, age at diagnosis, anatomical sub-site, histological sub-type) was examined. Three out of the 10 genes analyzed exhibited a marked hypermethylation, whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation, in gastric tumors. Among differentially methylated genes, we identified new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in GC, suggesting that epigenetic deregulation of these genes and their corresponding cellular pathways may promote the development and progression of GC. We also found that global demethylation of tumor cell genomes occurs in GC, consistent with the notion that abnormal hypermethylation of specific genes occurs concomitantly with genome-wide hypomethylation. Age and gender had no significant influence on methylation states, but an association was observed between LINE-1 and MLH1 methylation levels with histological sub-type and anatomical sub-site. This study identifies aberrant methylation patters in specific genes in GC thus providing information that could be exploited as novel biomarkers in clinics and molecular epidemiology of GC.


Affective certainty and congruency of touch modulate the experience of the rubber hand illusion.
Our sense of body ownership relies on integrating different sensations according to their temporal and spatial congruency. Nevertheless, there is ongoing controversy about the role of affective congruency during multisensory integration, i.e. whether the stimuli to be perceived by the different sensory channels are congruent or incongruent in terms of their affective quality. In the present study, we applied a widely used multisensory integration paradigm, the Rubber Hand Illusion, to investigate the role of affective, top-down aspects of sensory congruency between visual and tactile modalities in the sense of body ownership. In Experiment 1 (N = 36), we touched participants with either soft or rough fabrics in their unseen hand, while they watched a rubber hand been touched synchronously with the same fabric or with a 'hidden' fabric of 'uncertain roughness'. In Experiment 2 (N = 50), we used the same paradigm as in Experiment 1, but replaced the 'uncertainty' condition with an 'incongruent' one, in which participants saw the rubber hand being touched with a fabric of incongruent roughness and hence opposite valence. We found that certainty (Experiment 1) and congruency (Experiment 2) between the felt and vicariously perceived tactile affectivity led to higher subjective embodiment compared to uncertainty and incongruency, respectively, irrespective of any valence effect. Our results suggest that congruency in the affective top-down aspects of sensory stimulation is important to the multisensory integration process leading to embodiment, over and above temporal and spatial properties.


Antibiotic-Loaded Bone Cement in Prevention of Periprosthetic Joint Infections in Primary Total Knee Arthroplasty: A Register-based Multicentre Randomised Controlled Non-inferiority Trial (ALBA trial).
The current evidence on the efficacy of antibiotic-loaded bone cement (ALBC) in reducing the risk of periprosthetic joint infections (PJI) after primary joint reconstruction is insufficient. In several European countries, the use of ALBC is routine practice unlike in the USA where ALBC use is not approved in low-risk patients. Therefore, we designed a double-blinded pragmatic multicentre register-based randomised controlled non-inferiority trial to investigate the effects of ALBC compared with plain bone cement in primary total knee arthroplasty (TKA). A minimum of 9,172 patients undergoing full-cemented primary TKA will be recruited and equally randomised into the ALBC group and the plain bone cement group. This trial will be conducted in Norwegian hospitals that routinely perform cemented primary TKA. The primary outcome will be risk of revision surgery due to PJI at 1-year of follow-up. Secondary outcomes will be: risk of revision due to any reason including aseptic loosening at 1, 6, 10 and 20 years of follow-up; patient-related outcome measures like function, pain, satisfaction and health-related quality of life at 1, 6 and 10 years of follow-up; risk of changes in the microbial pattern and resistance profiles of organisms cultured in subsequent revisions at 1, 6, 10 and 20 years of follow-up; cost-effectiveness of routine ALBC versus plain bone cement use in primary TKA. We will use 1:1 randomisation with random permuted blocks and stratify by participating hospitals to randomise patients to receive ALBC or plain bone cement. Inclusion, randomisation and follow-up will be through the Norwegian Arthroplasty Register. The trial was approved by the Western Norway Regional Committees on Medical and Health Research Ethics (reference number: 2019/751/REK vest) on 21 June 2019. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. NCT04135170.


Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning.
Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia- and reperfusion-induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short-lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning. Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof-of-concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning.


A deep investigation into the adipogenesis mechanism: profile of microRNAs regulating adipogenesis by modulating the canonical Wnt/beta-catenin signaling pathway.
MicroRNAs (miRNAs) are a large class of tiny non-coding RNAs (approximately 22-24 nt) that regulate diverse biological processes at the posttranscriptional level by controlling mRNA stability or translation. As a molecular switch, the canonical Wnt/beta-catenin signaling pathway should be suppressed during the adipogenesis; However, activation of this pathway leads to the inhibition of lipid depots formation. The aim of our studies was to identify miRNAs that might be involved in adipogenesis by modulating WNT signaling pathway. Here we established two types of cell model, activation and repression of WNT signaling, and investigated the expression profile of microRNAs using microarray assay. The high throughput microarray data revealed 18 miRNAs that might promote adipogenesis by repressing WNT signaling: miR-210, miR-148a, miR-194, miR-322 etc. Meanwhile, we also identified 29 miRNAs that might have negative effect on adipogenesis by activating WNT signaling: miR-344, miR-27 and miR-181 etc. The targets of these miRNAs were also analysed by bioinformatics. To validate the predicted targets and the potential functions of these identified miRNAs, the mimics of miR-210 were transfected into 3T3-L1 cells and enlarged cells with distinct lipid droplets were observed; Meanwhile, transfection with the inhibitor of miR-210 could markedly decrease differentiation-specific factors at the transcription level, which suggested the specific role of miR-210 in promoting adipogenesis. Tcf7l2, the predicted target of miR-210, is a transcription factor triggering the downstream responsive genes of WNT signaling, was blocked at transcription level. Furthermore, the activity of luciferase reporter bearing Tcf7l2 mRNA 3' UTR was decreased after co-transfection with miR-210 in HEK-293FT cells. Last but not least, the protein expression level of beta-catenin was increased in the lithium (LiCl) treated 3T3-L1 cells after transfection with miR-210. These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2. The results suggest the presence of miRNAs in two cell models, providing insights into WNT pathway-specific miRNAs that can be further characterized for their potential roles in adipogenesis. To our knowledge, present study represents the first attempt to unveil the profile of miRNAs involved in adipogenesis by modulating WNT signaling pathway, which contributed to deeper investigation of the mechanism of adipogenesis.


Cell-free DNA testing: future applications in gastroenterology and hepatology.
The application of next-generation sequencing in clinical practice is increasing as accuracy and interpretation have improved and the cost continues to decline rapidly. Cell-free DNA is a unique source for next-generation sequencing that could change routine clinical practice in gastroenterology and hepatology. Testing of cell-free DNA in blood and fecal samples is an easy, rapid, and noninvasive method to assess for premalignant, malignant, metabolic, infectious, inflammatory, and autoimmune gastrointestinal and liver diseases. In this review, we describe cell-free DNA technologies, current applications of cell-free DNA testing, and proposed cell-free DNA targets for gastrointestinal and hepatic diseases, with a specific focus on malignancy. In addition, we provide commentary on how cell-free DNA can be integrated into clinical practice and help guide diagnosis, prognosis, disease management, and therapeutic response.


Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle.
The sensory organs of the inner ear possess resident populations of macrophages, but the function of those cells is poorly understood. In many tissues, macrophages participate in the removal of cellular debris after injury and can also promote tissue repair. The present study examined injury-evoked macrophage activity in the mouse utricle. Experiments used transgenic mice in which the gene for the human diphtheria toxin receptor (huDTR) was inserted under regulation of the Pou4f3 promoter. Hair cells in such mice can be selectively lesioned by systemic treatment with diphtheria toxin (DT). In order to visualize macrophages, Pou4f3-huDTR mice were crossed with a second transgenic line, in which one or both copies of the gene for the fractalkine receptor CX3CR1 were replaced with a gene for GFP. Such mice expressed GFP in all macrophages, and mice that were CX3CR1(GFP/GFP) lacked the necessary receptor for fractalkine signaling. Treatment with DT resulted in the death of ∼70% of utricular hair cells within 7 days, which was accompanied by increased numbers of macrophages within the utricular sensory epithelium. Many of these macrophages appeared to be actively engulfing hair cell debris, indicating that macrophages participate in the process of 'corpse removal' in the mammalian vestibular organs. However, we observed no apparent differences in injury-evoked macrophage numbers in the utricles of CX3CR1(+/GFP) mice vs. CX3CR1(GFP/GFP) mice, suggesting that fractalkine signaling is not necessary for macrophage recruitment in these sensory organs. Finally, we found that repair of sensory epithelia at short times after DT-induced hair cell lesions was mediated by relatively thin cables of F-actin. After 56 days recovery, however, all cell-cell junctions were characterized by very thick actin cables.


Magnesium use in asthma pharmacotherapy: a Pediatric Emergency Research Canada study.
To examine the use of intravenous magnesium in Canadian pediatric emergency departments (EDs) in children requiring hospitalization for acute asthma and association of administration of frequent albuterol/ipratropium and timely corticosteroids with hospitalization. Retrospective medical record review at 6 EDs of otherwise healthy children 2 to 17 years of age with acute asthma. Data were extracted on history, disease severity, and timing of ED stabilization treatments with inhaled albuterol, ipratropium, corticosteroids, and magnesium. Primary outcome was the proportion of hospitalized children given magnesium in the ED. Secondary outcome was the ED use of "intensive therapy" in hospitalized children, defined as 3 albuterol inhalations with ipratropium and corticosteroids within 1 hour of triage. A total of 19 (12.3%) of 154 hospitalized children received magnesium (95% confidence interval 7.1, 17.5) versus 2 of 962 discharged patients. Children given magnesium were more likely to have been previously admitted to ICU (odds ratio [OR] 11.2), hospitalized within the past year (OR 3.8), received corticosteroids before arrival (OR 4.0), presented with severe exacerbation (OR 6.1), and to have been treated at 1 particular center (OR 14.9). Forty-two (53%) of 90 hospitalized children were not given "intensive therapy." Children receiving "intensive therapy" were more likely to present with severe disease to EDs by using asthma guidelines (ORs 8.9, 3.0). Differences in the frequencies of all stabilization treatments were significant across centers. Magnesium is used infrequently in Canadian pediatric EDs in acute asthma requiring hospitalization. Many of these children also do not receive frequent albuterol and ipratropium, or early corticosteroids. Significant variability in the use of these interventions was detected.


Involvement in compensation litigation and outcome from an online pain management program.
To report on the effect of involvement in civil litigation on outcome for patients enrolled in a validated Internet-delivered pain management program, the Pain Course. Data from a randomized controlled trial (RCT) on the effect of varying levels of clinician support was used to examine the effect of involvement in civil litigation on outcome in a free online pain management course. Outcome measures were changes in scores on self-report questionnaires for depression, anxiety, and disability (PHQ-9, GAD-7, and RMDQ) from baseline to 3-month follow-up for those still involved in litigation and those who had completed litigation, compared with outcomes for those who did not report involvement in litigation. The use of regular and as-required opioid medication at assessment and follow-up were also compared. Of the 397 patients enrolled in the pain course, 290 (73.0%) were not involved in litigation, 80 (20.2%) reported involvement in litigation that had been resolved and 27 (6.8%) reported ongoing litigation. Those still involved in litigation had the highest scores on depression scales and the highest rate of opioid use. The completion rates and symptom improvement was lower among current litigants but were still positive, with effect sizes on the outcome measures of between 0.56 and 0.73, as well as a reduction in the use of opioids. Current involvement in compensation litigation was associated with lower treatment completion and less symptom improvement. Nevertheless, the positive findings have significant implications for people involved in workers' compensation and other litigation who report pain as one of their symptoms. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.
Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.


Effects of UV radiation and diet on polyunsaturated fatty acids in the skin, ocular tissue and dorsal muscle of Atlantic salmon (Salmo salar) held in outdoor rearing tanks.
The effect of UV radiation (UVR) on juvenile Atlantic salmon (Salmo salar) was assessed by measuring the fatty acid (FA) profiles of muscle, dorsal and ventral skin, and ocular tissues following 4-month long exposures to four different UVR treatments in outdoor rearing tanks. Fish were fed two different diets (Anchovy- and Herring-oil based) that differed in polyunsaturated fatty acid (PUFA) concentrations. Anchovy-fed salmon had higher concentrations of ALA (alpha-linoleic acid; 18:3n-3), EPA (eicosapentaenoic acid; 20:5n-3) and DPA (docosapentaenoic acid, 22:5n-3) in their muscle tissues than fish fed the Herring feed. Fish subjected to enhanced UVB levels had higher concentrations of LIN (linolenic acid, 18:2n-6) and ALA, total omega-6 FA and SAFA (saturated fatty acids) in their tissues compared with fish in reduced UV treatments. Concentrations of ALA, LIN, GLA (gamma-linolenic acid; 18:3n-6), EPA, PUFA and total FA were higher in ventral skin of fish exposed to enhanced UVB compared with fish in reduced UV treatments. Salmon exposed to reduced UV weighed more per-unit-length than fish exposed to ambient sunlight. The FA profiles suggest that fish exposed to UV radiation were more quiescent than fish in the reduced UV treatments resulting in a buildup of catabolic substrates.


A 90-day OECD TG 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (CHTP1.2) compared with cigarette smoke. II. Systems toxicology assessment.
Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. Here, we report the results from the systems toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Transcriptomics, proteomics, and lipidomics analyses complemented the standard endpoints. In the respiratory nasal epithelium, CS induced an adaptive tissue and inflammatory response, which was much weaker after CHTP1.2 aerosol exposure, mostly limited to the highest CHTP1.2 concentration (at twice the 3R4F CS concentration: 50 vs. 23 μg nicotine/L), in female rats. In the lungs, the effects of CS exposure included inflammatory and cellular stress responses, which were absent or much lower after CHTP1.2 aerosol exposure. Outside of the respiratory tract, CS and CHTP1.2 aerosol induced effects that were previously associated with exposure to any nicotine-containing aerosol, e.g., lower lipid concentrations in serum. Overall, this systems toxicology analysis complements and confirms the results from classical toxicological endpoints and further suggests potentially reduced respiratory health risks of CHTP1.2.


Diversity of HLA among Taiwan's indigenous tribes and the Ivatans in the Philippines.
Taiwan's indigenous tribes, especially the east coast tribes are not only closely related to Oceania but also with the Australian aborigines. The Ivatans of the Batan Islands in the Philippines are closely related to the Yami tribe of Taiwan as cultural and anthropological studies have shown. Many DRB1 alleles (*15021, *16021, *0404, *04051, *11011, *12021, *1401, *08032) have high allele frequencies (>20%) in certain tribes, suggesting Taiwan's indigenous tribes are homogeneous populations. These high frequency DRB1 alleles and also some HLA-A-B-DR haplotypes found in Taiwan's indigenous tribes are also found in Oceania, Australian aborigines, south and north east Asians and American Indians, lending further support to our previous findings that Taiwan's indigenous tribes are more or less genetically related to both northern and southern Asians, possibly as well as Amerindians. HLA-A*2402 with a remarkably high frequency among Taiwan's indigenous tribes (52.1% approximately 86.3%), especially the central mountain tribes, possibly represents not only founder effects and population bottlenecks, but also positive selection of the allele. Although the Ami tribe has the highest ever reported frequencies of the DRB1*0404 and DRB1*0405, these alleles have not been found to be associated with rheumatoid arthritis as previously described for Caucasians. In addition, DRB1*1401 has a high frequency in most tribes but is not associated with psoriasis as previously indicated in some studies, suggesting the involvement of some additional genetic and/or environmental factors mechanism in the development of these diseases.


The rare Arg181Cys mutation in the μ opioid receptor can abolish opioid responses.
Genetic variability contributes to variable clinical response to opioids. This study emerged from the observation of three Norwegian patients who showed no or extraordinary poor response to very high doses of opioids. We suspected a genetic defect and applied a 'most likely candidate gene' approach to investigate this possibility. DNA sequencing was used to search for mutations in coding regions of the OPRM1 gene, encoding the μ opioid receptor (hMOR), in one patient. The remaining two patients, and two cohorts comprising 2158 European cancer pain patients and 600 Norwegian healthy volunteers, respectively, were genotyped using a custom-made TaqMan SNP allelic discrimination assay. DNA sequencing disclosed a homozygous, inactivating Arg181Cys mutation in hMOR in the patient who showed no effects from opioids. The two patients with poor effect from very high doses of opioids were both heterozygous for the mutation. Six heterozygous patients identified among the European cancer patients all used high doses of opioids and/or reported inferior effect on their pain. About one in every 100 Norwegians is heterozygous for the mutation. The Arg181Cys mutation occurs at clinically relevant frequencies and produces a signaling dead hMOR which may abolish or significantly reduce opioid effects in affected individuals. Anesthesiologists and practitioners in pain medicine should be aware of this mutation as a possible explanation for inefficiency of opioids and consider genotyping in relevant cases. Individuals homozygous for the mutation may need a highly personalized approach to pain therapy.


Evaluation of a point-of-care blood analyzer and determination of reference ranges for blood parameters in rockfish.
To compare values of blood parameters in rockfish obtained by use of a point-of-care portable blood analyzer with values determined by a veterinary diagnostic laboratory, calculate reference ranges for various blood parameters in black rockfish, and compare values of blood parameters in clinically normal fish with those of fish with clinical abnormalities. Prospective study. 41 captive adult black rockfish (Sebastes melanops) and 4 captive adult blue rockfish (Sebastes mystinus). Rockfish were anesthetized with tricaine methanesulfonate for collection of blood samples. Heparinized blood samples were immediately analyzed with a point-of-care analyzer. Blood sodium, potassium, chloride, urea nitrogen, and glucose concentrations; Hct; pH; partial pressure of carbon dioxide; total carbon dioxide concentration; bicarbonate concentration; base excess; and hemoglobin concentration were determined. A microhematocrit technique was used to determine PCV, and a refractometer was used to estimate total plasma protein concentration. Paired heparinized blood samples were transported to a veterinary diagnostic laboratory for analyses. Data obtained with the point-of-care analyzer were reproducible; however, values for most blood parameters were significantly different from those obtained by the veterinary diagnostic laboratory. Fish with poor body condition had several blood parameter values that were lower than corresponding values in clinically normal fish. Point-of-care blood analyses may prove useful in rockfish. Point-of-care data for a large number of clinically normal fish must be obtained for reference ranges to be calculated, and further assessments of clinically abnormal fish are necessary to determine the relevance of the data.


From ultraviolet to Prussian blue: a spectral response for the cyanotype process and a safe educational activity to explain UV exposure for all ages.
Engaging students and the public in understanding UV radiation and its effects is achievable using the real time experiment that incorporates blueprint paper, an "educational toy" that is a safe and easy demonstration of the cyanotype chemical process. The cyanotype process works through the presence of UV radiation. The blueprint paper was investigated to be used as not only engagement in discussion for public outreach about UV radiation, but also as a practical way to introduce the exploration of measurement of UV radiation exposure and as a consequence, digital image analysis. Tests of print methods and experiments, dose response, spectral response and dark response were investigated. Two methods of image analysis for dose response calculation are provided using easy to access software and two methods of pixel count analysis were used to determine spectral response characteristics. Variation in manufacture of the blueprint paper product indicates some variance between measurements. Most importantly, as a result of this investigation, a preliminary spectral response range for the radiation required to produce the cyanotype reaction is presented here, which has until now been unknown.


Molecular mechanisms of metal toxicity and carcinogenesis.
Many metals and metal-containing compounds have been identified to be potent mutagens and carcinogens. Recently, a new sub-discipline of molecular toxicology and carcinogenesis has been developed. The combination of newly developed molecular techniques and free radical approach makes it possible to insightfully examine metal-induced carcinogenesis in precise molecular terms so that intricate biological interrelationships can be elucidated. In consideration of the increased amount of new findings deciphered by utilizing these new methods, the 1st Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis was held. In this conference, more than 50 scientists from nine countries presented their novel discoveries concerning metal-induced carcinogenesis, delineated molecular mechanism of metal carcinogenesis, and proposed novel therapeutic intervention and prevention strategies. This article reviews some of the state-of-the-art information presented at the meeting regarding the molecular mechanisms of metal cytotoxicity and carcinogenesis.


Addressing access barriers to health services: an analytical framework for selecting appropriate interventions in low-income Asian countries.
While World Health Organization member countries embraced the concept of universal coverage as early as 2005, few low-income countries have yet achieved the objective. This is mainly due to numerous barriers that hamper access to needed health services. In this paper we provide an overview of the various dimensions of barriers to access to health care in low-income countries (geographical access, availability, affordability and acceptability) and outline existing interventions designed to overcome these barriers. These barriers and consequent interventions are arranged in an analytical framework, which is then applied to two case studies from Cambodia. The aim is to illustrate the use of the framework in identifying the dimensions of access barriers that have been tackled by the interventions. The findings suggest that a combination of interventions is required to tackle specific access barriers but that their effectiveness can be influenced by contextual factors. It is also necessary to address demand-side and supply-side barriers concurrently. The framework can be used both to identify interventions that effectively address particular access barriers and to analyse why certain interventions fail to tackle specific barriers.


Glucose monitoring using a polymer brush modified polypropylene hollow fiber-based hydraulic flow sensor.
Tight regulation of blood glucose levels of diabetic patients requires durable and robust continuous glucose sensing schemes. This manuscript reports the fabrication of ultrathin, phenylboronic acid (PBA) functionalized polymer brushes that swell upon glucose binding and which were integrated as the sensing interface in a new polypropylene hollow fiber (PPHF)-based hydraulic flow glucose sensor prototype. The polymer brushes were prepared via surface-initiated atom transfer radical polymerization of sodium methacrylate followed by postpolymerization modification with 3-aminophenyl boronic acid. In a first series of experiments, the glucose-response of PBA-functionalized poly(methacrylic acid) (PMAA) brushes grafted from planar silicon surfaces was investigated by quartz crystal microbalance with dissipation (QCM-D) and atomic force microscopy (AFM) experiments. The QCM-D experiments revealed a more or less linear change of the frequency shift for glucose concentrations up to ∼10 mM and demonstrated that glucose binding was completely reversible for up to seven switching cycles. The AFM experiments indicated that glucose binding was accompanied by an increase in the film thickness of the PBA functionalized PMAA brushes. The PBA functionalized PMAA brushes were subsequently grafted from the surface of PPHF membranes. The hydraulic permeability of these porous fibers depends on the thickness and swelling of the PMAA brush coating. PBA functionalized brush-coated PPHFs showed a decrease in flux upon exposure to glucose, which is consistent with swelling of the brush coating. Because they avoid the use of enzymes and do not rely on an electrochemical transduction scheme, these PPHF-based hydraulic flow sensors could represent an interesting alternative class of continuous glucose sensors.


Regulation of phosphorylation of aminoacyl-tRNA synthetases in the high molecular weight core complex in reticulocytes.
Five aminoacyl-tRNA synthetases found in the high molecular weight core complex were phosphorylated in rabbit reticulocytes following labeling with 32P. The synthetases were isolated by affinity chromatography on tRNA-Sepharose followed by immunoprecipitation. The five synthetases phosphorylated were the glutamyl-, glutaminyl-, lysyl-, and aspartyl-tRNA synthetases and, to a lesser extent, the methionyl-tRNA synthetase. In addition, a 37,000-dalton protein, associated with the synthetase complex and tentatively identified as casein kinase I, was also phosphorylated in intact cells. Phosphoamino acid analysis of the proteins indicated all of the phosphate was on seryl residues. Incubation of reticulocytes with 32P in the presence of 8-bromo-cAMP and 3-isobutyl-1-methylxanthine resulted in a 6-fold increase in phosphorylation of the glutaminyl-tRNA synthetase and a 2-fold increase in phosphorylation of the aspartyl-tRNA synthetase. When the high molecular weight core complex was isolated by gel filtration/affinity chromatography, the profile of phosphorylation was similar to that observed by immunoprecipitation with a 9- and 3-fold stimulation of the glutaminyl- and aspartyl tRNA-synthetase, respectively. From this data it was concluded that the increased phosphorylation of the glutaminyl- and aspartyl-tRNA synthetases obtained with 8-bromo-cAMP did not appear to be involved in dissociation of the high molecular weight core complex.


Prescription Opioid Abuse in Chronic Pain: An Updated Review of Opioid Abuse Predictors and Strategies to Curb Opioid Abuse: Part 1.
Chronic pain and prescription opioid abuse are extremely prevalent both in this country and worldwide. Consequences of opioid misuse can be life-threatening with significant morbidity and mortality, exacting a heavy toll on patients, physicians, and society. Individuals with chronic pain and co-occurring substance use disorders and/or mental health disorders, are at a higher risk for misuse of prescribed opioids. Opioid abuse and misuse occurs for a variety of reasons, including self-medication, use for reward, compulsive use because of addiction, and diversion for profit. There is a significant need for treatment approaches that balance treating chronic pain; while minimizing risks for opioid abuse, misuse, and diversion. The use of chronic opioid therapy for chronic non-cancer pain has increased dramatically in the past 2 decades in conjunction with associated increases in the abuse of prescribed opioids and accidental opioid overdoses. Consequently, a validated screening instrument which provides an effective and rational method of selecting patients for opioid therapy, predicting risk, and identifying problems once they arise could be of enormous benefit in clinical practice. Such an instrument could potentially curb the risk of iatrogenic addiction. Although several screening instruments and strategies have been introduced in recent years, there is no single test or instrument which can reliably and accurately predict those patients not suitable for opioid therapy or identify those who need increased vigilance or monitoring during therapy. At present, screening for opioid abuse includes assessment of premorbid and comorbid substance abuse; assessment of aberrant drug-related behaviors; risk factor stratification; and utilization of opioid assessment screening tools. Multiple opioid assessment screening tools and instruments have been developed by various authors. In addition, urine drug testing, monitoring of prescribing practices, prescription monitoring programs, opioid treatment agreements, and utilization of universal precautions are essential. Presently, a combination of strategies is recommended to stratify risk, to identify and understand aberrant drug related behaviors, and to tailor treatments accordingly. This manuscript builds on the 2012 opioid guidelines published in Pain Physician and the 2016 guidelines released by the Centers for Disease Control and Prevention. It reviews the current state of knowledge regarding the growing problem of opioid abuse and misuse; known risk factors; and methods of predicting, assessing, monitoring, and addressing opioid abuse and misuse in patients with chronic non-cancer pain.Key words: Opioids, misuse, abuse, chronic pain, prevalence, risk assessment, risk management, drug monitoring, aberrant drug-related behavior.


Exopolysaccharides favor the survival of Erwinia amylovora under copper stress through different strategies.
Erwinia amylovora causes fire blight, a destructive disease of rosaceous plants very difficult to control. We demonstrated that copper, employed to control plant diseases, induces the "viable-but-nonculturable" (VBNC) state in E. amylovora. Moreover, it was previously reported that copper increases production of its main exopolysaccharide (EPS), amylovoran. In this work, the copper-complexing ability of amylovoran and levan, other major EPS of E. amylovora, was demonstrated. Following this, EPS-deficient mutants were used to determine the role of these EPSs in survival of this bacterium in AB mineral medium with copper, compared to their wild type strain and AB without copper. Total, viable and culturable counts of all strains were monitored for six months. With copper, a larger fraction of the viable population of EPS mutants entered into the VBNC state, and earlier than their wild type strain, showing the contribution of both EPSs to long-term survival in a culturable state. Further, we demonstrated that both EPSs can be used as carbon source by E. amylovora under deprivation conditions. Overall, these previously unreported functions of amylovoran and levan provide survival advantages for E. amylovora, which could contribute to its enhanced persistence in nature.


Stiffness of the arterial wall, joints and skin in women with a history of pre-eclampsia.
The epidemiology of pre-eclampsia suggests a constitutional component for the disorder. We have recently shown an association for blood pressure (BP) with stiffness of joints and skin in adolescents, suggesting that constitutionally determined stiffness of body tissues is associated with blood pressure. Therefore, we compared stiffness of the arterial wall, joints and skin between women with a history of pre-eclampsia and women with an uncomplicated pregnancy. Cases were 44 women with a history of early onset pre-eclampsia and controls were 46 women with a history of uncomplicated pregnancy. Arterial stiffness was determined non-invasively with pulse wave velocity measurement. As a measure of capsule and ligament stiffness, the active range of motion of various joints was measured. Skin stiffness was measured using a tissue compliance meter. Analysis of variance (ANOVA) multiple comparison tests were used for comparison of the study groups. Linear regression models were used to determine the associations between stiffness parameters and possible confounders. For the cases, body mass index (BMI) was significantly higher and age and parity were significantly lower. BP was significantly higher for the cases. Stiffness of the arterial wall, joints and skin were significantly higher. After adjustment for mean arterial pressure, stiffness of the joints and skin were significantly higher, but no difference remained for arterial stiffness. Women with a history of pre-eclampsia had a significantly higher stiffness of the arterial wall, joints and skin compared with controls. This suggests a constitutionally determined stiffness of connective tissues in former pre-eclamptic cases.


PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis.
The aim of this study was to analyse the safety and efficacy of the PegIFNα/ribavirin/protease inhibitor combination in severe and/or refractory hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis. This prospective cohort study included 30 patients (median age 59 years [53-66] and 57% of women) with HCV-MC vasculitis. PegIFNα/ribavirin (for 48 weeks) was associated with telaprevir (375 mg three times daily, for 12 weeks, [n = 17]) or boceprevir (800 mg three times daily, for 44 weeks, (n = 13]). Twenty three patients (76.7%) were non-responders to previous antiviral therapy. At week 72, twenty patients (66.7%) were complete clinical and sustained virological responders. The cryoglobulin level decreased from 0.45 to 0 g/L (p<0.0001) and the C4 level increased from 0.09 to 0.14 g/L (p = 0.017). Complete clinical responders had a higher frequency of purpura (16/20 [80%] vs. 4/10 [40%], p = 0.045), and a trend towards lower frequency of neuropathy (9/20 (45%) vs. 8/10 [80%], p = 0.12) compared with partial responders. Serious adverse events occurred in 14 patients (46.6%) during the 72 weeks of follow-up. Twenty eight patients (93.3%) received erythropoietin, 14 (46.6%) had red blood cell transfusion and 2 (6.6%) received granulocyte stimulating agent. The baseline factors associated with serious adverse events included liver fibrosis (p = 0.045) and a low platelet count (p = 0.021). The PegIFNα/ribavirin/protease inhibitor combination is highly effective in severe and/or refractory HCV-MC at the cost of frequent side effects. Baseline platelet count and liver fibrosis are useful in guiding treatment decisions.


Vitamin D and barrier function: a novel role for extra-renal 1 alpha-hydroxylase.
Much recent attention has focused on the positive health benefits of vitamin D beyond its established role in calcium homeostasis. Epidemiology has highlighted the link between vitamin D deficiency and prevalent diseases such as common cancers and autoimmune disease. Furthermore, studies in vitro have shown that the active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a potent antiproliferative and immunosuppressive agent. The net effect of this has been the generation and analysis of synthetic analogues of vitamin D for potential use in the treatment of cancers and other disorders including psoriasis. However, there is increasing interest in the impact that vitamin D may have on normal physiology above and beyond its classical effects on calcium homeostasis and bone metabolism. We have postulated that these 'non-calcemic' effects of vitamin D are dependent on extra-renal synthesis of 1,25(OH)(2)D(3) via the enzyme 1 alpha-hydroxylase at barrier sites throughout the body. Here we present a review of the mechanisms associated with extra-renal 1 alpha-hydroxylase, and we also speculate on how this 'new' physiological role for vitamin D may actually reflect an ancient function for this pluripotent secosteroid.


Medical malpractice and meningiomas: an analysis of 47 cases.
Among medical practices, surgical fields, including neurosurgery, are at a high risk for medical malpractice litigation. With meningiomas contributing to 10% of the total neurosurgery litigation cases, the aim of this study was to identify demographic characteristics, reasons for litigation, and surgical complications commonly reported in these cases. This analysis serves to increase neurosurgeons' awareness of factors associated with medical malpractice litigation. The online legal database Westlaw was utilized to query public litigation cases related to the medical management of meningiomas between December 1985 and May 2020. Variables extracted included the following: plaintiff and defendant demographics, litigation category, plaintiff medical complaints, and trial outcomes. The authors compared these characteristics between cases with decisions in favor of the defendant and those with decisions in favor of the plaintiff. A total of 47 cases met the inclusion criteria. Failure to diagnose (68.1%) was the most common type of malpractice claim, and surgical complications (19.1%), motor weakness (33%), and financial loss (33%) were cited as the most common postoperative complaints. Individual specialties that most often required defense due to malpractice claims were radiology (21.7%) and neurosurgery (19.6%). The jury verdict was in favor of the defense in 51.1% of cases and in favor of the plaintiff in 27.7% of cases. A settlement was reached in 19.1% of cases. The mean payout for a verdict in favor of the plaintiff was $3,409,650.22, while the mean payout for settlements was $867,555.56. The greatest average payout for specialties was in neurosurgery at $3,414,400, followed by radiology at $3,192,960. Cases with a verdict in favor of the plaintiff were more likely to involve an internal medicine physician as a defendant (p = 0.007). Over one-half of the cases resulted in a defendant's verdict with failure to diagnose cited as the most common reason for litigation. Radiology and neurosurgery were the most common specialties for legal cases and also had some of the largest average payouts based on specialty. Motor weakness and financial loss were the most common plaintiff postoperative complaints. These findings may inform surgeons on active measures to take, such as increasing focus on diagnostic accuracy and reducing specific postoperative complaints, such as motor weakness, through risk management and prophylactic measures, to reduce unfavorable legal outcomes.


Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.


Combined Effects of MMP-7, MMP-8 and MMP-26 on the Risk of Ischemic Stroke.
Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.


Review: the net benefits of depression management in primary care.
Depression is often diagnosed and treated in primary care settings. Organizational and systems interventions that restructure primary care practices and train staff have been shown to be cost-effective strategies for treating depression. Funders are increasingly calling for a cost-benefit assessment of such programs. In this study, the authors review existing cost-effectiveness studies of primary care depression treatments, classify them into categories, translate the results into net benefit terms, and assess whether more costly programs generate greater net benefit. The authors find that interventions that provide training to primary care teams in how to manage depression most consistently produce net benefits, with more costly interventions of this type generating larger net benefits than less costly interventions. Collaborative care interventions, which add specialized staff to primary care practices, and therapy interventions, in which clinicians are trained to provide therapy, also generate net social benefits at conventional valuations of quality-adjusted life years.


Determination of microcystin-LR in waters in the subnanomolar range by sol-gel imprinted polymers on solid contact electrodes.
The present work reports new sensors for the direct determination of Microcystin-LR (MC-LR) in environmental waters. Both selective membrane and solid contact were optimized to ensure suitable analytical features in potentiometric transduction. The sensing layer consisted of Imprinted Sol-Gel (ISG) materials capable of establishing surface interactions with MC-LR. Non-Imprinted Sol-Gel (NISG) membranes were used as negative control. The effects of an ionic lipophilic additive, time of sol-gel polymerization, time of extraction of MC-LR from the sensitive layer, and pH were also studied. The solid contact was made of carbon, aluminium, titanium, copper or nickel/chromium alloys (80 : 20 or 90 : 10). The best ISG sensor had a carbon solid contact and displayed average slopes of 211.3 mV per decade, with detection limits of 7.3 × 10(-10) M, corresponding to 0.75 μg L(-1). It showed linear responses in the range of 7.7 × 10(-10) to 1.9 × 10(-9) M of MC-LR (corresponding to 0.77-2.00 μg L(-1)), thus including the limiting value for MC-LR in waters (1.0 μg L(-1)). The potentiometric-selectivity coefficients were assessed by the matched potential method for ionic species regularly found in waters up to their limiting levels. Chloride (Cl(-)) showed limited interference while aluminium (Al(3+)), ammonium (NH(4)(+)), magnesium (Mg(2+)), manganese (Mn(2+)), sodium (Na(+)), and sulfate (SO(4)(2-)) were unable to cause the required potential change. Spiked solutions were tested with the proposed sensor. The relative errors and standard deviation obtained confirmed the accuracy and precision of the method. It also offered the advantages of low cost, portability, easy operation and suitability for adaptation to flow methods.


Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease.
In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).


A revolution of photovoltaics: persistent electricity generation beyond solar irradiation.
Renewable energy utilization by energy conversion devices is regarded as a promising solution to resolve energy crisis and environmental pollution problems. Solar energy occupies 99% of the total energy of the Earth; therefore, the development of photovoltaic technology to convert solar energy into electricity is attracting considerable interests. The state-of-the-art research in this field mainly focuses on the improvement of power conversion efficiency under the sunlight irradiation by new materials development, device structure optimization, technique innovation, etc. In real natural environments, there is no or negligible sunlight for at least half of the time, particularly during rainy, foggy days or at night. Therefore, it is a challenging but promising strategy to develop new-type solar cells that can persistently harvest waste energies from nature without sacrificing the solar-to-electric conversion ability. In theory, these photovoltaics may break through the theoretical efficiency limitation and maximize the total power output. In this frontier article, the status quo of these physical proof-of-concept hybrid solar cells as well as the preparation methods of the solar cell architectures, and why harvesting waste energies are discussed. According to the working principles, the possible strategies of improving waste energy conversion efficiency are also envisaged.


How much flower-rich habitat is enough for wild pollinators? Answering a key policy question with incomplete knowledge.
In 2013, an opportunity arose in England to develop an agri-environment package for wild pollinators, as part of the new Countryside Stewardship scheme launched in 2015. It can be understood as a 'policy window', a rare and time-limited opportunity to change policy, supported by a narrative about pollinator decline and widely supported mitigating actions. An agri-environment package is a bundle of management options that together supply sufficient resources to support a target group of species. This paper documents information that was available at the time to develop such a package for wild pollinators. Four questions needed answering: (1) Which pollinator species should be targeted? (2) Which resources limit these species in farmland? (3) Which management options provide these resources? (4) What area of each option is needed to support populations of the target species? Focussing on wild bees, we provide tentative answers that were used to inform development of the package. There is strong evidence that floral resources can limit wild bee populations, and several sources of evidence identify a set of agri-environment options that provide flowers and other resources for pollinators. The final question could only be answered for floral resources, with a wide range of uncertainty. We show that the areas of some floral resource options in the basic Wild Pollinator and Farmland Wildlife Package (2% flower-rich habitat and 1 km flowering hedgerow), are sufficient to supply a set of six common pollinator species with enough pollen to feed their larvae at lowest estimates, using minimum values for estimated parameters where a range was available. We identify key sources of uncertainty, and stress the importance of keeping the Package flexible, so it can be revised as new evidence emerges about how to achieve the policy aim of supporting pollinators on farmland.


Human and chimpanzee shared and divergent neurobiological systems for general and specific cognitive brain functions.
A long-standing topic of interest in human neurosciences is the understanding of the neurobiology underlying human cognition. Less commonly considered is to what extent such systems may be shared with other species. We examined individual variation in brain connectivity in the context of cognitive abilities in chimpanzees (n = 45) and humans in search of a conserved link between cognition and brain connectivity across the two species. Cognitive scores were assessed on a variety of behavioral tasks using chimpanzee- and human-specific cognitive test batteries, measuring aspects of cognition related to relational reasoning, processing speed, and problem solving in both species. We show that chimpanzees scoring higher on such cognitive skills display relatively strong connectivity among brain networks also associated with comparable cognitive abilities in the human group. We also identified divergence in brain networks that serve specialized functions across humans and chimpanzees, such as stronger language connectivity in humans and relatively more prominent connectivity between regions related to spatial working memory in chimpanzees. Our findings suggest that core neural systems of cognition may have evolved before the divergence of chimpanzees and humans, along with potential differential investments in other brain networks relating to specific functional specializations between the two species.


Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T- and B-cell tolerance to islet xenografts.
Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation.


Differential effects of digitalis on chemoreflex responses in humans.
To investigate the effects of digitalis on chemoreflexes in humans, we measured muscle sympathetic nerve activity (microneurography), minute ventilation, oxygen saturation, end-tidal carbon dioxide, mean arterial pressure, heart rate, and central venous pressure during stimulation of peripheral chemoreceptors with hypoxia, during stimulation of central chemoreceptors with hypercapnia, and during a cold pressor test before and after digitalis and placebo in 10 healthy volunteers on two different days (randomized, double-blind, cross-over design). Digitalis did not affect baseline measurements significantly. Despite similar changes in oxygen saturation and end-tidal carbon dioxide during hypoxia and hypercapnia with both placebo and digitalis, digitalis significantly potentiated overall ventilatory responses to hypoxia (+67 +/- 12% before versus +98 +/- 3% after digitalis; mean +/- SEM; P < .01) but did not affect the response to hypercapnia. Sympathetic nerve activity increased by 25 +/- 9% during hypoxia before digitalis and 30 +/- 10% during hypoxia after digitalis (P = NS) and increased by 38 +/- 18% during hypercapnia before digitalis and 26 +/- 11% during hypercapnia after digitalis (P = NS). Digitalis did not significantly change responses to the cold pressor test. Placebo had no effect on ventilatory and sympathetic nerve activity responses. We conclude that digitalis selectively augments ventilatory responses to peripheral chemoreceptor stimulation by hypoxia.


Integration of an academic medical center and a community hospital: the Brigham and Women's/Faulkner hospital experience.
Brigham and Women's Hospital (BWH), a major academic tertiary medical center, and Faulkner Hospital (Faulkner), a nearby community teaching hospital, both in the Boston, Massachusetts area, have established a close affiliation relationship under a common corporate parent that achieves a variety of synergistic benefits. Formed under the pressures of limited capacity at BWH and excess capacity at Faulkner, and the need for lower-cost clinical space in an era of provider risk-sharing, BWH and Faulkner entered into a comprehensive affiliation agreement. Over the past seven years, the relationship has enhanced overall volume, broadened training programs, lowered the cost of resources for secondary care, and improved financial performance for both institutions. The lessons of this relationship, both in terms of success factors and ongoing challenges for the hospitals, medical staffs, and a large multispecialty referring physician group, are reviewed. The key factors for success of the relationship have been integration of training programs and some clinical services, provision of complementary clinical capabilities, geographic proximity, clear role definition of each institution, commitment and flexibility of leadership and medical staff, active and responsive communication, and the support of a large referring physician group that embraced the affiliation concept. Principal challenges have been maintaining the community hospital's cost structure, addressing cultural differences, avoiding competition among professional staff, anticipating the pace of patient migration, choosing a name for the new affiliation, and adapting to a changing payer environment.


Immunosuppression management in renal transplant recipients with normal-immunological risk: 10-year results from the Swiss Transplant Cohort Study.
Primary maintenance immunosuppressive therapies for renal transplant recipients underwent significant changes in recent years. We aimed to assess time trends and the impact of immunosuppressive regimens in first renal transplant recipients without immunological risk (blood group incompatibility, pre-existing donor-specific antibodies, positive B/T cell cross-match) in a prospective national multicentre cohort. The Swiss Transplant Cohort Study (STCS) prospectively enrols all patients receiving solid organ transplants in Switzerland since 2008 and systematically collects high quality clinical and laboratory data using standardised definitions. The current STCS nested study enrolled all adult transplant-naïve normal-immunological risk renal transplant recipients up to the end of 2017 and investigated different immunosuppressive strategies across a variety of transplantation relevant outcomes. Of 1191 recipients enrolled at six transplant centres, 115 (10%) died with a functioning allograft and 92 (8%) lost their allograft during a median follow-up time of 5.8 years. The predominant immunosuppressive therapy comprised tacrolimus, mycophenolate mofetil and prednisone (73.7%), whereas 24.3% were treated with ciclosporin instead of tacrolimus. Primary immunosuppression with an mTOR inhibitor (1.1%) or other immunosuppressive combinations (0.8%) was rare. In the years following 2011, ciclosporin-based immunosuppression decreased significantly. The incidence of graft loss was significantly higher in patients with ciclosporin-based than with tacrolimus-based immunosuppression (adjusted hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.29–2.14; p <0.01), but the occurrence of acute transplant rejections did not differ significantly (adjusted HR 1.48, 95% CI 0.82–2.65; p = 0.19). The longitudinal course of the renal allograft function was significantly better (p = 0.013) in recipients of tacrolimus-based immunosuppressive therapy. Graft failure-free survival was higher (HR 1.25, 95% CI 0.97– 1.6; p = 0.08) with tacrolimus-based than with ciclosporin-based immunosuppression. Cytomegalovirus infections occurred more frequently with ciclosporin-based immunosuppression (9.7% vs 6.4% after 1 year), whereas the incidence of BK virus infections was similar in both groups. The median time to prednisone discontinuation was 1.9 years and did not differ between the two groups. Eleven cases of post-transplantation lymphoproliferative disorder were observed during the follow-up period (1 with ciclosporin-based and 10 with tacrolimus-based immunosuppression). The available data show that primary maintenance immunosuppression with tacrolimus has displaced ciclosporin-based therapies. The tacrolimus-based immunosuppression therapy showed consistently better results across almost all assessed clinically relevant outcomes. (ClinicalTrials.gov Number: NCT01204944).


3,4-N-methlenedioxymethamphetamine-induced hypophagia is maintained in 5-HT1B receptor knockout mice, but suppressed by the 5-HT2C receptor antagonist RS102221.
3,4-Methylenedioxy-N-methamphetamine (MDMA or 'ecstasy') is a psychoactive substance, first described as an appetite suppressant in humans, inducing side effects and even death. MDMA increases serotonin (5-HT) levels, and 5-HT inhibits food intake, but the 5-HT receptors involved in MDMA-induced changes in feeding behavior are unknown. We examined whether a systemic MDMA injection would reduce the physiological drive to eat in starved mice and tested if the inactivation of 5-HT1B or 5-HT2C receptors could restore this response. Our results indicate that in starved mice, MDMA (10 mg/kg) provoked an initial hypophagia for 1 h (-77%) followed by a period of hyperphagia (studied between 1 and 3 h). This biphasic feeding behavior due to MDMA treatment was maintained in 5-HT1B receptor-null mice or in animals treated with the 5-HT1B/1D receptor antagonist GR127935 (3 or 10 mg/kg). In contrast, MDMA-induced hypophagia (for the first 1 h period) was suppressed when combined with the 5-HT2C receptor antagonist RS102221 (2 mg/kg). However, RS102221 did not alter MDMA-induced hyperphagia (for the 1-3 h period) but did exert a stimulant effect, when administered alone, during that period. We have previously shown that MDMA or 5-HT1A/1B receptor agonist RU24969 fails to stimulate locomotor activity in 5-HT1B receptor-null mice. Our present data indicate that the 5-HT2C receptor antagonist RS102221 suppresses MDMA-induced hyperlocomotion. These findings provide the first evidence that the inactivation of 5-HT2C receptors may reduce hypophagia and motor response to MDMA, while a genetic deficit or pharmacological inactivation of 5-HT1B receptors was insufficient to alter the feeding response to MDMA.


Trypanosoma brucei: immunisation with plasmid DNA encoding invariant surface glycoprotein gene is able to induce partial protection in experimental African trypanosomiasis.
Trypanosoma brucei is the etiological agent responsible for African trypanosomiasis, an infectious pathology which represents a serious problem of public health and economic losses in Sub-Saharan Africa. As one of the foremost neglected illnesses, few resources have been available for the development of vaccines or new drugs, in spite of the current therapeutical drugs showing little efficiency and high toxicity. Hence, it is obviously important to widen effective therapeutics and preventive strategies against African trypanosomiasis. In this work, we use the DNA vaccine model to evaluate immunisation effectiveness in mice challenged with Trypanosoma brucei brucei. We demonstrate that Balb/C mice immunised intramuscularly with a single dose of a DNA plasmid encoding a bloodstream-stage specific invariant surface glycoprotein (ISG) are partially protected from a lethal dose of T. b. brucei. Interestingly, the surviving animals show high levels of IgG2a anti-trypanosoma antibodies, suggesting that the Th1 response profile seems important for the induced mechanisms of immune protection.


Examining motorcyclists' postcrash impressions: A qualitative study.
Motorcycle-related crashes and injuries continue to be of great concern in Iran. This study seeks to explore how motorcyclists' perspectives and impressions of a crash are shaped and influence their future riding behaviors. This was a qualitative study conducted in 3 major cities in Iran between March 2011 and February 2012. Participants included 31 male motorcyclists, of whom 22 participated in 4 focus groups and 9 in in-depth interviews. Findings were derived through the thematic method of analysis. Six delineated themes suggest different factors that influence riders' postcrash impressions. These include (1) opposing reactions from family and peers postcrash; (2) the motorcyclist's perception of his or her ability to handle risky road situations; (3) risk-taking attributes; (4) perceived responsibility in meeting family needs; (5) the severity of the crash-related injury; and (6) elapsed time from the crash experience. Riders' postcrash impressions were formed by the opposing reactions of their family and peers to the crash experience (i.e., the index crash); the personality of riders, including being overconfident and a risk taker; familial obligations; feeling traumatized by the crash; and passage of time. These formed their perceptions, feelings, attitudes, and thoughts about the index crash. These findings are an important step in understanding how perception and attitudes of motorcyclists are shaped and how these influence their future riding behavior. The needs for interventional studies to assess the effectiveness of road safety risk reduction programs aligned with the riders' degree of postcrash impressions are discussed.


Disinhibitory reactions to benzodiazepines: a review.
This article reviews some of the important aspects of benzodiazepine-induced disinhibitory reactions. Although reactions of this type are relatively rare, they may sometimes manifest themselves in aggressive behavior accompanied by suicidal or homicidal tendencies. It appears that these reactions occur more commonly in younger patients, although the elderly (above 65 years) may also be at risk. Many mechanisms have been postulated, but none truly explain how these reactions arise. The concept that central cholinergic mechanisms may play a role, however, remains attractive and stems primarily from physostigmine's ability to successfully reverse this type of reaction. The potential role of the benzodiazepine antagonists, eg, flumazenil, in reversing disinhibitory reactions is also discussed. Apart from patients who previously exhibited poor impulse control, there are no reliable indicators for recognizing potential candidates for this type of reaction. To minimize the occurrence of disinhibitory reactions, some guidelines, which include the avoidance of certain drug combinations, the use of low doses of benzodiazepines, slow incremental intravenous administration, and good rapport with patients, are presented.


Vigilant at the end of life: family advocacy in the nursing home.
Increasing numbers of Americans die in nursing homes. Little is known about the roles and experiences of family members of persons who die in nursing homes. The authors conducted 54 qualitative telephone interviews of close family or friends of individuals who had spent at least 48 hours in the last month of life in a nursing home. Respondents had earlier participated in a national survey that found 587 of 1578 decedents (37.2%) received end-of-life nursing home care. In qualitative interviews respondents described the last year of life, focusing on the nursing home experience. Interviews were analyzed by a multidisciplinary team to identify key themes of areas of concern. An important interview theme revealed families often felt the need to advocate for their dying relative because of low expectations or experiences with poor quality nursing home care. They noted staff members who did not fully inform them about what to expect in the dying process. Respondents reported burden and gratification in care they themselves provided, which sometimes entailed collaboration with staff. Interviews also identified ways hospice care impacted families, including helping to relieve family burden. End-of-life advocacy takes on increased urgency when those close to the dying resident have concerns about basic care and do not understand the dying course. Enhancing communication, preparing families at the end of life, and better understanding of hospice are likely to increase family trust in nursing home care, improve the care of dying residents, and help reduce family burden.


Genetic parameters for concentrations of minerals in longissimus muscle and their associations with palatability traits in Angus cattle.
The objective of this study was to estimate genetic parameters for concentrations of minerals in LM and to evaluate their associations with beef palatability traits. Samples of LM from 2,285 Angus cattle were obtained and fabricated into steaks for analysis of mineral concentrations and for trained sensory panel assessments. Nine minerals, including calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sodium, and zinc, were quantified. Restricted maximum likelihood procedures were used to obtain estimates of variance and covariance components under a multiple-trait animal model. Estimates of heritability for mineral concentrations in LM varied from 0.01 to 0.54. Iron and sodium were highly and moderately heritable, respectively, whereas the other minerals were lowly heritable except for calcium, copper, and manganese, which exhibited no genetic variation. Strong positive genetic correlations existed between iron and zinc (0.49, P < 0.05), between magnesium and phosphorus (0.88, P < 0.05), between magnesium and sodium (0.68, P < 0.05), and between phosphorus and potassium (0.69, P < 0.05). Overall tenderness assessed by trained sensory panelists was positively associated with manganese, potassium, and sodium and negatively associated with phosphorus and zinc concentrations (P < 0.05). Juiciness assessed by trained sensory panelists was negatively associated with magnesium and positively associated with manganese and sodium concentrations (P < 0.05). Livery or metallic flavor was not associated with any of the minerals (P > 0.05). Beefy flavor was positively associated with calcium, iron, and zinc and negatively associated with sodium concentration, whereas a painty or fishy flavor was positively associated with sodium and negatively associated with calcium and potassium concentrations (P < 0.05). Beef is a major contributor of iron and zinc in the human diet, and these results demonstrate sufficient genetic variation for these traits to be improved through marker-assisted selection programs without compromising beef palatability.


The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants.
Oral poliovirus vaccine is less immunogenic and effective in low-income countries than in high-income countries, similarly to other oral vaccines. The high prevalence of intestinal pathogens and associated environmental enteropathy has been proposed to explain this problem. Because administration of an antibiotic has the potential to resolve environmental enteropathy and clear bacterial pathogens, we aimed to assess whether antibiotics would improve oral poliovirus vaccine immunogenicity. We did a double-blind, randomised, placebo-controlled trial of the effect of azithromycin on the immunogenicity of serotype-3 monovalent oral poliovirus vaccine given to healthy infants living in 14 blocks of Vellore district, India. Infants were eligible to participate if they were 6-11 months old, available for the study duration, and lacked serum neutralising antibodies to serotype-3 poliovirus. Infants were randomly assigned (1:1) at enrolment to receive oral 10 mg/kg azithromycin or placebo once daily for 3 days, followed by serotype-3 monovalent oral poliovirus vaccine on day 14. The primary outcome was detection of serum neutralising antibodies to serotype-3 poliovirus at a dilution of one in eight or more on day 35 and was assessed in the per-protocol population (ie, all those who received azithromycin or placebo, oral poliovirus vaccine, and provided a blood sample according to the study protocol). Safety outcomes were assessed in all infants enrolled in the study. The trial is registered with the Clinical Trials Registry India, number CTRI/2014/05/004588. Between Aug 5, 2014, and March 21, 2015, 754 infants were randomly assigned: 376 to receive azithromycin and 378 to placebo. Of these, 348 (93%) of 376 in the azithromycin group and 357 (94%) of 378 infants in the placebo group completed the study per protocol. In the azithromycin group, 175 (50%) seroconverted to serotype-3 poliovirus compared with 192 (54%) in the placebo group (risk ratio 0·94, 95% CI 0·81-1·08; p=0·366). Azithromycin reduced faecal biomarkers of environmental enteropathy (calprotectin, myeloperoxidase, α1-antitrypsin) and the prevalence of bacterial but not viral or eukaryotic pathogens. Viral pathogens were associated with lower seroconversion. Three serious adverse events were reported (two in the azithromycin group and one in the placebo group), but none was considered related to the study interventions. Azithromycin did not improve the immunogenicity of oral poliovirus vaccine despite reducing biomarkers of environmental enteropathy and the prevalence of pathogenic intestinal bacteria. Viral interference and innate antiviral immune mechanisms might be more important determinants of the immunogenicity of live-virus oral vaccines. Bill & Melinda Gates Foundation.


Involvement of ATM missense variants and mutations in a series of unselected breast cancer cases.
It has been proposed that women carrying heterozygous mutations of the ATM gene could be at increased risk of developing breast cancer. However, data in the literature are contrasting and no firm conclusion has been reached. Our aim was to verify whether ATM inactivation could play a role in breast tumor development. Following the classical tumor suppressor inactivation scheme, tumors showing loss of heterozygosity (LOH) at the ATM locus should present an increased proportion of mutated ATM forms. We screened a cohort of 173 nonselected primary breast tumors for LOH in a 4 cM region at 11q23 spanning the ATM gene. We analyzed 25 tumors presenting LOH within the ATM locus for mutations in the ATM coding sequence using an RT-PCR-SSCP approach. Five patients were found to bear a coding missense variant, out of which four corresponded to a frequent polymorphism in exon 39. One patient presented a previously unreported variant in exon 19 (2614C>T) resulting in a nonconservative change (Pro>Ser) at aa 872. This variant was not found in any of the other 172 patients nor in 63 healthy controls tested, indicating that it is a rare ATM variant. LOH involved the ATM wild-type allele in the tumor presenting variant 2614. However, because the ATM gene presents a relatively large number of rare coding polymorphism it is difficult, in the absence of familial data, to be conclusive on the significance of this variant. Searching for further variants in exons 19 and 39 in the whole set of 173 breast tumors, we found one tumor showing an acquired deletion of four bases in the ATM gene. Somatic mutations affecting the ATM gene thus seem rare in breast cancer. In our cohort of breast cancer patients, tumors presenting LOH at the ATM locus did not show an increased frequency of sequence variants. Furthermore, allelic imbalance profiles in a 4-cM region of chromosome arm 11q spanning the ATM locus revealed that hot spots of LOH were more likely to correspond to a region localized telomeric to the gene. Therefore, these data suggest that other target genes for genetic inactivation exist in the 11q23 region.


Reference curves for the Gross Motor Function Measure: percentiles for clinical description and tracking over time among children with cerebral palsy.
Physical therapists frequently use the 66-item Gross Motor Function Measure (GMFM-66) with the Gross Motor Function Classification System (GMFCS) to examine gross motor function in children with cerebral palsy (CP). Until now, reference percentiles for this measure were not available. The aim of this study was to improve the clinical utility of this gross motor measure by developing cross-sectional reference percentiles for the GMFM-66 within levels of the GMFCS. A total of 1,940 motor measurements from 650 children with CP were used to develop percentiles. These observations were taken from a subsample, stratified by age and GMFCS, of those in a longitudinal cohort study reported in 2002. A standard LMS (skewness-median-coefficient of variation) method was used to develop cross-sectional reference percentiles. Reference curves were created for the GMFM-66 by age and GMFCS level, plotted at the 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97th percentiles. The variability of change in children's percentiles over a 1-year interval also was investigated. The reference percentiles extend the clinical utility of the GMFM-66 and GMFCS by providing for appropriate normative interpretation of GMFM-66 scores within GMFCS levels. When interpreting change in percentiles over time, therapists must carefully consider the large variability in change that is typical among children with CP. The use of percentiles should be supplemented by interpretation of the raw scores to understand change in function as well as relative standing.